This Program Project Grant is focussed on the development of more effective cancer therapies through integrated and yet diversified contributions of various laboratories of the Department of Experimental Therapeutics and Grace Cancer Drug Center (GCDC) at Roswell Park. New compounds and biologicals are obtained within this program or from outside sources. Emphasis is given on 1) development of therapeutic treatments based on differential sensitivity to differentiation factors of different tissues, 2) development of new inhibitors of protein kinase C, 3) evaluation of the therapeutic potential of intervention on folate polyglutamate metabolism, and 4) verification of therapeutic potential of combination treatments including biological response modifiers (BRM) and identification of BRM correlates of antitumor action. In this proposal, additional emphasis is given to opportunities to modify resistance towards therapeutic applications. The antitumor activity of treatment developed as indicated above obtained from RO-1 supported research in the GCDC is evaluated in vitro and in vivo tumor spectrum. The preclinical toxicology and pharmacology of treatments of interest are studies in different animal species prior to clinical trials. The development of new treatment is integrated closely with both basic progress in the biochemical pharmacology of anticancer drugs and fundamental studies on the regulation of cell metabolism carried out with other grant support in the GCDC: interactions among these approaches and sources of support provide an optimal background for the formulation of new ideas and implementation of studies leading to advances in the therapy of cancer. This Program Project is focused on the development of new treatments of cancer. During the current period of support, the main research emphasis has been on the development of new compounds and treatments developed as a part of this program. Other leads originated in GCDC in RPMI research supported by other funds, or were obtained from outside sources. In some cases the emphasis was on investigations of the biochemical and biological basis for the development of new treatment, in some it was concerned with actual treatment evaluation and development. During the five years of support requested herein, these two main approaches are expected to be continued with added emphasis on the problem of drug resistance and ways to overcome.